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The lipoatrophy (also known as lipodystrophy) syndromes are a heterogeneous group of syndromes characterized by a paucity of adipose or fat tissue. Metabolic abnormalities may also be associated with this condition. These metabolic abnormalities include hypertriglyceridemia and severe insulin resistance usually accompanied by diabetes mellitus (Reitmann et al., 2000). Lipoatrophy in humans may be genetically inherited or acquired. There is more than one genetic form of lipoatrophy. For example, mutations in the gene encoding Lamin A/C (LMNA) has been shown to be associated with the Dunnigan-type familial partial lipodystrophy (FPLD) (Cao et al., 2000). Individuals with Dunnigan's FPLD are born with a normal fat distribution, but at puberty, they develop progressive subcutaneous extremity and truncal fat loss, with sparing of visceral and head and neck adipose tissue. A different chromosomal location (9q34) has also been linked to a disease gene for congenital generalized lipodystrophy (Garg et al., 1999). Congenital generalized lipodystrophy is a recessive disorder characterized by a near complete absence of adipose tissue from birth, insulin resistance, hypertriglyceridemia and acanthosis nigricans.
Some forms of lipoatrophy in humans are acquired. For example, many patients infected with human immunodeficiency virus (HIV) and treated with highly active antiretroviral therapy (HAART) develop a partial lipodystrophy, characterized by loss of subcutaneous fat from the face, extremities and trunk, with increased visceral fat and a ‘buffalo hump’ similar to that seen in Cushing's syndrome. These patients may also develop metabolic disorders such as insulin resistance and hypertriglyceridemia. Acquired forms of lipoatrophy may also be associated with juvenile dermamyositis and other autoimmune diseases.
Investigations in animal models have demonstrated that these metabolic abnormalities may be associated with fat loss (Gavrilova et al., 2000). But insulin resistance and hypertriglyceridemia that characterize lipoatrophy have been extremely refractory to treatment, even though a variety of approaches have been tried (Garg, 2000). One of these approaches includes treatment with thiazolidinediones, which are PPARγ (peroxisome proliferator activated receptor γ) agonists. While thiazolidinediones are appealing because they promote both adipocyte differentiation and insulin sensitivity, patients receiving thiazolidinediones are usually managed with combination therapy, including high dose insulin, oral hypoglycemic agents (e.g. metformin and thiazolidinediones), and lipid-lowering drugs, (e.g., fibrates and statins). Despite these therapies, patients with generalized lipoatrophy continue to manifest severe hypertriglyceridemia (which causes recurrent attacks of acute pancreatitis), severe hyperglycemia (which poses risk of diabetic retinopathy and nephropathy), and non-alcoholic steatohepatitis (which can result in cirrhosis) (Arioglu et al., 2000). In fact, one member of the thiazolidinediones, troglitazone, was removed from the US market because of its rare but severe hepatotoxicity, leaving two thiazolidinediones (rosiglitazone and pioglitazone) available (Reitmann, et al.). Thus, there exists a need for an alternative treatment to lipoatrophy.
A variety of genetically engineered animal models for lipoatrophy have been developed and tested. These models, however, provide conflicting results as to the sensitivity of these animals to treatment with leptin. For example, in one transgenic mouse model, which expresses a truncated nuclear version of SREBP-1 c and mimics the features of congenital generalized lipodystrophy having insulin resistance and markedly low adipose tissue, continuous systemic infusion of leptin overcame the resistance of the mice to insulin (Shimomura et al., 1999). On the other hand, a different transgenic mouse, which expresses the A-ZIP/F-1 gene and characterized by lack of fat tissue, severe resistance to insulin, diabetes, and greatly reduced serum leptin levels, failed to respond to leptin at similar doses and were minimally effective at higher doses (Gavrilova et al., 2000). Any efficacy with leptin also diminished with age of the animal (Id.). Furthermore, although insulin resistance was overcome with leptin in the SREBP-1c transgenic mice, reversal of lipoatrophy was not observed (Shimomura et al.).
Current use of leptin in human therapy has mainly been focused on reducing obesity and its associated metabolic dysfunction (Heymsfield et al. 1999). Patients with absence of leptin due to mutations in the leptin gene are morbidly obese from infancy and have a number of hormonal abnormalities including insulin resistance and hypogonadotropic hypogonadism (Montague et al., 1997). Physiological replacement with recombinant leptin for one year in one of these patients caused significant weight reduction and improvement in the hormonal abnormalities (Farooqi et al., 1999; PCT App. No.: WO 00/20872). These previous studies have not addressed the use of leptin in the context of human lipoatrophy.